Manufacture of Small Molecule APIs

Examples of some of the typical violations leading to drug product recall according to the FDA (1996) are  

By 2004, the FDA intends to develop a more detailed model for cGMP inspections centered on the risk-based approach. 

4 MANUFACTURE OF SMALL MOLECULE APIS (CHEMICAL SYNTHESIS METHODS) 

The reaction vessel is normally made of glass-lined stainless steel with a jacket for heating and cooling and consists of  

Chapter 10 Good Manufacturing Practice Drug Manufacturing 

---

Manufacture of Small Molecule APIs (Chemical Synthesis Methods) 332... 

The manufacturing process for a small molecule API is shown in Figure 10.3. Typically, the chemical reactions are performed in large reaction vessels. For commercial production of an API, the reaction vessel can typically range from 1000 L to 20 000 L in volume (Figure 10.4). 

This section will discuss selected topics pertaining to scale-up and transfer of enzy-mahc processes for small-molecule API manufacture from laboratory to pilot plant and full commercial scale. 

Organic Chemistry Synthesis Route The production of the API for small molecule drugs requires ingenious and meticulous development of organic synthesis steps. Some drugs may require more than 50 steps to obtain the intended API. For example, there are more than 100 production steps for the manufacture of Roche s AIDS drug enfuvirtide (Fuzeon), approved by the FDA in March 2003 see Exhibit 10.1. 

Small-molecule manufacturing is also a system of checks and balances in which any small increase or decrease in reaction step performance can have consequences downstream. As always, patient safety is of utmost concern. Any manufacturing process changes that alter an impurity level or introduce a new impurity, even as low as 0.1%, may necessitate additional toxicity studies and documentation for review and registration. In addition, an improvement in reaction efficiency may alter bulk product crystallinity or polymorph composition that can affect formulation and human pharmacokinetics. Once process parameters are finalized, the ultimate manufacturing step involves selection of a manufacturing site, transfer of the process, and preparation of a demonstration batch followed by a minimum of three consecutive validation batches of API to demonstrate that the synthesis of material can be controlled within analytical specifications and reproducibility. 

The observation of multiple charging of proteins in electrospray ionization attracted much attention all major instrument manufacturers introduced an API system to be used in combination with an electrospray interface. At the same time, it was found that electrospray ionization is not only suitable for the mass analysis of large molecules, but is also a very efficient ionization technique of small polar or ionic molecules, e.g. drugs and their metabolites. In the past few years, hundreds of dedicated API-MS systems equipped with electrospray and APCI interfaces have found their way into many different laboratories, especially within pharmaceutical companies and biochemistry/biotechnology laboratories. 

One remarkable achievement of red biotechnology was that, although costs in drug development exploded, the costs for process development of manufacturing processes for proteins were reduced over time. This should also be the goal for small molecule pharmaceuticals, which represent the majority of active pharmaceutical ingredients (APIs). The sustainable production of affordable pharmaceuticals and health-care products should be a priority for biotechnology These objectives are... 

---